ABSTRACT The epidemics of opioid prescribing, injection drug use, overdose, and infectious disease transmission intersect in rural America. Clinical trials methods have not yet caught up with shifting trends in Opioid Use Disorder (OUD) and its consequences. Research methods to study People Who Use Drugs (PWUD) were crafted in urban settings, and cannot simply be imported to rural communities which differ demographically, socioculturally, and in infrastructure. Optimal strategies for recruiting and retaining people with OUD in clinical research in rural America remain unknown. The proposed Peer-based Retention Of people who Use Drugs in Rural Research (PROUD-R2) study tests strategies to improve retention of PWUD in research in rural communities, and fosters facilitation of rural participants into clinical trials. This study leverages the national Rural Opioids Initiative infrastructure in Oregon and Appalachian Kentucky and Ohio. The Rural Opioids Initiative is a multi-state consortium studying access to care and prevention of overdose and infectious consequences of opioid use in rural America. The initiative recruits PWUD in rural settings using harmonized respondent-driven sampling (RDS) for risk behavior assessments. RDS is a widely used network-based sampling technique for hard-to-reach populations in which purposively sampled initial participants are given a limited number of referral coupons to recruit peers, who in turn recruit more peers until the desired sample size is reached. Peers can successfully reach and engage hard-to-reach populations in treatment, but their potential to improve integration of special populations in clinical trial implementation and retention has been largely untapped. Clinical and Translational Science Award (CTSA) sites and the NIDA Clinical Trials Network are well-positioned to partner with Rural Opioids Initiative investigators to determine optimal practices for recruiting and retaining rural PWUD in research and transferring clinical research innovations to PWUD in rural communities. PROUD-R2 uses a rigorous, two-arm, cluster-randomized trial of RDS chains to receive brief video training and support in peer retention techniques. Intervention arm participants are tasked with and incentivized for retaining recruited peers at 6- and 12-months (n=685 participants) in addition to standard retention strategies. Control RDS chains receive standard retention strategies including a harmonized staff outreach approach (e.g., phone calls, text message reminders) (n=685 participants). We compare study retention at 6 and 12-months (primary outcome) (Aim 1), assess preferences and willingness to participate in future clinical trials using a survey including discrete choice experiments (Aim 2), and explore perceptions of research participation and retention using in-depth qualitative interviews (Aim 3). The project informs methods to optimize engagement in research for PWUD in rural America and has the potential to transform retention strategies in clinical trials. PROUD-R2 aligns with NCATS priorities to improve retention of difficult to reach populations in rural areas of the country most impacted by OUD.